P1160: METHOTREXATE IN COMBINATION WITH IBRUTINIB, THIOTEPA, RITUXIMAB (R-MTO) FOLLOWED BY AUTOLOGOUS STEM-CELL TRANSPLANT FOR PRIMARY CNS LYMPHOMA
Authors: LI-Jie Xing, Hai-Chen Wei, Dan Liu, Hui Wang, Ping LI, Lin-Na Xie, Zeng-Jun LI
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive B-cell malignancy. Despite the possibility of a cure, the prognosis remains poor. The standard treatment includes high-dose methotrexate and rituximab, followed by consolidation with either whole brain radiation therapy or autologous stem cell transplantation. However, there is still no clear consensus on the best treatment approach. We added thiotepa chemotherapy to the induction regimen to improve outcomes, as it has shown promising activity in inhibiting tumor growth by disrupting DNA bonds. We also included orelabrutinib, a novel and potent BTK inhibitor with high cerebrospinal fluid concentrations, which has demonstrated efficacy in treating PCNSL. Aims: Thus, we conducted a clinical study to evaluate the efficacy and safety of a combination regimen of thiotepa, orelabrutinib, and methotrexate with rituximab (R-MTO) followed by autologous hematopoietic stem cell transplantation in patients with PCNSL. Methods: This is an ongoing, single-center, single-arm, open-label study. Patients (aged 18-80 years) with PCNSL received 5-6 cycles of R-MTO regimen (rituximab 375 mg/m2 iv day 0; MTX 3.5 g/m2 iv day1; thiotepa, 30-40 mg/m2, d4; orelabrutinib 150 mg qd po; 3 weeks per cycle) as the induction therapy between April 2022 and February 2023. It was proposed to receive orelabrutinib monotherapy as maintenance after R-MTO therapy for up to 2 years. Efficacy was assessed by MRI/PET per the International PCNSL Collaborative Group (IPCG) criteria. Patients not suffering disease progression subsequently received consolidation treatment with high-dose chemotherapy (HCT) plus ASCT, including busulfan 3.2 mg/kg (days -5, -4), thiotepa 250 mg/m2 (days -7, -6), cytarabine 2g/m2 q12h (days -3, -2), and reinfusion of stem cells (day 0). The primary endpoint was progression-free survival (PFS) at 2 years by intention-to-treat (ITT). Secondary endpoints included complete response (CR) rate, overall response rate (ORR); overall survival (OS) and toxicities. Results: Between April 2022 and February 2023, a total of 15 patients with PCNSL were enrolled in our study, including 11 who were newly diagnosed and had not received any prior treatment. Of these patients, 12 completed four cycles of treatment, including all 11 of the newly diagnosed patients. The median age of the patients was 57 years (range: 36-72) and 7/12 (58.3%) were male. By data cutoff, 9/12(75%) patients had completed six cycles of treatment, 3/12 (25%) had completed 4 cycles of treatment. The ORR was 91.7% (11/12), and CR rate was 91.7% (11/12). One patient with P53 mutation progressed after 2 cycles of treatment and died 3.8 months after diagnosis. Of the nine patients who completed six cycles of treatment, six were evaluated, and all of them (100%) achieved CR. Additionally, among the five patients who underwent autologous HSCT, all of them (100%) remained CR. The most common hematological adverse events associated with the R-MTO regimen were mild to moderate (grade 1-2) decreases in neutrophil count, which typically resolved within a few days. Summary/Conclusion: The R-MTO induction treatment has demonstrated efficacy to achieve higher responses rate in patients with PCNSL and the associated adverse events are manageable.Keywords: Hematopoietic cell transplantation, CNS lymphoma, Methotrexate